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N Engl J Med. 2016 Sep 22;375(12):1131-41. doi: 10.1056/NEJMoa1607887. Epub 2016 Aug 30.

Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors.

Author information

1
From the Population Health Research Institute, McMaster University, Hamilton ON, Canada (S.J.C., J.W.E., D.M.S., E.Z., B.M., J.N., W.T.L., M.C.); Seton Dell Medical School Stroke Institute, Austin, TX (T.J.M.); Harvard Medical School, Boston (C.M.G.); Portola Pharmaceuticals, San Francisco (J.T.C., A.G., M.D.B., G.L., P.B.C., S.G., J.L., B.L.W.); University of Leuven, Leuven, Belgium (P.V.); Centre Hospitalier Universitaire de Clermont-Ferrand, Clermont-Ferrand (J.S.), and Grenoble-Alpes University Hospital, Grenoble (P.A.) - both in France; Academic Medical Center, Amsterdam (S.M.); Guy's and St. Thomas' Hospitals, King's College London, London (A.T.C.); University Hospital Carl Gustav Carus Dresden, Dresden, Germany (J.B.-W.); and Hospital Universitario La Paz, Madrid (J.L.-S.).

Abstract

BACKGROUND:

Andexanet alfa (andexanet) is a recombinant modified human factor Xa decoy protein that has been shown to reverse the inhibition of factor Xa in healthy volunteers.

METHODS:

In this multicenter, prospective, open-label, single-group study, we evaluated 67 patients who had acute major bleeding within 18 hours after the administration of a factor Xa inhibitor. The patients all received a bolus of andexanet followed by a 2-hour infusion of the drug. Patients were evaluated for changes in measures of anti-factor Xa activity and were assessed for clinical hemostatic efficacy during a 12-hour period. All the patients were subsequently followed for 30 days. The efficacy population of 47 patients had a baseline value for anti-factor Xa activity of at least 75 ng per milliliter (or ≥0.5 IU per milliliter for those receiving enoxaparin) and had confirmed bleeding severity at adjudication.

RESULTS:

The mean age of the patients was 77 years; most of the patients had substantial cardiovascular disease. Bleeding was predominantly gastrointestinal or intracranial. The mean (±SD) time from emergency department presentation to the administration of the andexanet bolus was 4.8±1.8 hours. After the bolus administration, the median anti-factor Xa activity decreased by 89% (95% confidence interval [CI], 58 to 94) from baseline among patients receiving rivaroxaban and by 93% (95% CI, 87 to 94) among patients receiving apixaban. These levels remained similar during the 2-hour infusion. Four hours after the end of the infusion, there was a relative decrease from baseline of 39% in the measure of anti-factor Xa activity among patients receiving rivaroxaban and of 30% among those receiving apixaban. Twelve hours after the andexanet infusion, clinical hemostasis was adjudicated as excellent or good in 37 of 47 patients in the efficacy analysis (79%; 95% CI, 64 to 89). Thrombotic events occurred in 12 of 67 patients (18%) during the 30-day follow-up.

CONCLUSIONS:

On the basis of a descriptive preliminary analysis, an initial bolus and subsequent 2-hour infusion of andexanet substantially reduced anti-factor Xa activity in patients with acute major bleeding associated with factor Xa inhibitors, with effective hemostasis occurring in 79%. (Funded by Portola Pharmaceuticals; ANNEXA-4 ClinicalTrials.gov number, NCT02329327 .).

PMID:
27573206
PMCID:
PMC5568772
DOI:
10.1056/NEJMoa1607887
[Indexed for MEDLINE]
Free PMC Article

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